Steroid hydroxythioesters



restrs hav ng an unsubstituted a "Er'diip, "a double bond,

' isnot'eorivertedto hydroity; other iatented Sept. 4, 1951 UNITED STATES PATENT "oFFICE" 'Rbtea ii. Levi A. vem McInto h, in, and ro, Kalamazoo, Mi'ch., 'as'sig'no'rs I n flompany, Kalamazoo, Mich., a corporation (Michigan No-brawing. Application September 15, 1947,

Serial No. 774,174

The present invention relates to [a hovel process for the preparation ofpr'e'g'h'he 'thioe ydroxyl and a 0-20 "side-chain or the formula -0 oHiy,.---yi-sn wherein n is a zero, one, or two and his 'athio- "alcohol residue.

, It is an object of the present invention "'to'pro- "vide a novel process for the coriver'sidn 6f '2. 3-

- forrnoxy-pregnane having a '5 double bond aiid pregnane nu iisothe'r than 11011 especial object oi the inye tio'n 'isft'h' pro sie'n of "a fsuch; process whereby "the "th'ioeste is produced with concomitant conversion or the 3 for noxy group to hydroxy, while an additieiial ac'yrox-y, including rormaxy, group atth'e ll-'- or 12-position in the unsaturated pregame nucleus,

mveriuon win become apparent n I g It has new beenieund that, when a pregnant: derivative fhav'ing a a-rormox'y group, a s doubie bond, and a gsmemhqm of the remain (CH2)i=COX, wherein X 'is 'h'Ydroxi/l or halogen and M's zero, one, or two, is re a'mereaptan 1n the resence or an a 'age itfisn h as pyridine, subsmutdpyfldmeeurmemyimiume, qiiliioline. sodium 'bieirlio'n t8 magnesium or ealciu'nroxide, not esteriflcation aecbmbusued. but the 3 The E6 01' ritrastilii gly.

a, trim-- this observation resides in 12 Claims. (01. cow-397.1) I

n of me armory "group *with 20 of the pregnane nucleus.

several valuable applications. First, the conversion of a 3-formoxy acid or acid halide to the 3- hydroiiy thioester may be conducted in a single step, instead of two separate steps. Second, where another acyloxy substituent is present in the pregnane nucleus, e. g., at the 0-11 or 6-12 position, the present invention accomplishes selective preparation of a thioester having 3-hydroiiy and 11- or 12 -acy1oxy substituents, thereby allowing variations to be effected between the C 3 and C-11 or 12-acy1oxy groups. Previously. it has been necessary to convert the B-acyloxy group to hydroxyl by hydrolysis, which also resulted in hydrolysis of other acyloxy groups in the pregnane nucleus, and subsequent acylation converted both hydro'xy groups to the same acyloxy radical. The importance of the present invention shoul'd therefore be-obvious, as it allows novel modifications of steroid nuclei for the preparation of hormone intermediates.-

The starting acids "and acid halides are known compounds. These may be, for example, any of the cholenic, nor-cholenic, or bisnor-cholenic acids or acid halides having a 3-formoxy group. Hydroxy, alkoxy, halogen, and other acyloxy, including formoxy, groups may be present in the unsaturated pregnane nucleus at positions other than the G 3 position. Likewise, other unsaturated compounds, such as 3-formoxy-(delta 5,7) -choladi enic acids and acid halides, may be employed. Prerequisites for the starting material are that it contain a 3-forrnoxy group, a 5-6 double bond, and an acid or acid halide group- 2 ing in the side-chain attached to carbon atom e A convenient method of preparing 3-formoxy compounds is by heating the 3-hydroxy acid with concentrated -mo'xy-12-benzoy10xy-(delta 5) bisnorr cholenic acid chloride, 3-formoxy-ll-hydroxy-(delta 5)- bisnor-cholenic acid chloride, 3-formoxy-l2-ace- 'toxy-(delta 5) -bisnor-cholenic acid chloride, 3- iormoxy ll propionoxy-(delta 5) nor-cholenic "acid chloride, and 3,11-diformoxy-(de1ta 5)- oxy acid or acid halide preferably the 1atter,'--..

usually in an organic solvent, such as anhydrous benzene, toluene, xylene, ether, or petroleum hyvg'irocarbons, with the desired organic acid-binding agent and a selected mercaptan of thQfOfmula R-SH. wherein R is an organic residue of a thioalcohol. B. may be, for example, alkyl, e. g.,

methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, n-octyl, dodecyl, or the like; cycloalkyl, e. g., cyclopentyl, cyclohexyl; cycloalkyl-alltyl,

e. g., cyclohexylmethyl; aryl, e. g., phenyl,-naphthyl; or aralykyl, e. g., benzyl or phenethyl. Unsaturated aliphatics and cycloaliphatics may also be employed, provided the required starting material is available. Substituted hydrocarbon radicals, e. g., chlorobenzyl, nitrophenyl, bromoethyl, aminopropyl, are also satisfactory. 3 The choice of R in the mercaptan is arbitrary, availability of the mercaptan being theonly limitin ct Equimolar proportions of reactants are satisfactory, but an excess of mercaptan may some-,

times be used to advantage. The reaction mixture is allowed to stand at about room temperature, 15-30 hours usually being suflicient time for reaction. Gentle heating sometimes increases the reaction rate, but is not usually necessary The reaction product may be worked up with water'and organic solvent,.e. g., ether, acqueous portions extracted, and combined organic layer vwashed with water, dilute'alkali, dilute acid, and

again with water. After drying the neutral frac-. tionand evaporating solvent, the residual oil may be crystallized from a suitablesolvent, e. g., alcohol, to yield the desired thioester, usually a stable solid.

The quantity of acid-binding agent necessary for accomplishment of the objectives of the pres- .ent invention may be varied over, a considerable range. It is only necessary that sufficient acidbinding agent be present to render the reaction mixture slightly basic, while the upper limit is usually, though not always necessarily, a p11 of about 10. The basicity is critical to the extent that it should be less than that which causes hydrolysis of the thioeste-r linkage.

The following examples'are given to illustrate the practice of the present invention, but are a in no way to be-construed as'limiting.

Example 1 Ethyl 3 -beta-hydrbzy- (delta 5) thiocholenate of water, giving 23 grams ('72 per cent) of ethyl 3-beta-ht'droxy-(delta 5) -thiocholenate, M, .P.

98-100 degrees centigrade. Several recrystallizations from hexane-benzene raised the melting point to 1085-1095 degrees centigrade.

Example 2.-M ethyl 3-hydroxy-11 formo.ry= (delta 5) -n0r-thiocholenat 'In the manner itsi vjh; for Example 1; this'co'mpound is prepared from 3,11-diformoxy- (delta 5)-nor-cholenic acid chloride (prepared by formylation of 3, ll-dihydroxy-(delta 5) -cholenic acidand' treatment of the product with thionyl chloride) and methyl mercaptan in the presence of'pyridine:

It is to be understood that the invention is not limited to the exact details of operation or compounds shown and described, as obvious modifications and-substitution of equivalents may be made in the invention without departing from thepspirit or scope thereof, which will be apparent to one skilled in the art, and we therefore limit ourselves only as defined in the appended claims.

a m= Y Y. f f 1 1. The process which includes 'thioesterifying an unsaturated derivative of the pregnane series, containing a C 5-6'double bond and'a 0-20 sidechain of the formula: --(CH2)n-COX,' wherein X is elected from hydroxyl and halogen, and n is selected from zero,- one, and two; while simultaneously deformylatinga forrnoxy group at the C-3 carbon atom of the pregane nucleus to a hydroxyl group by reacting the pregnane derivative with a mercaptan in the presence of an acid-binding agent. f i 1 2. The process which includes:' thioesterifying an unsaturated pregnane derivative, containing ja C 5'-6doubl e bond'and a 0-20 side-chain of the formula; -'(CH 2). CQX, wherein X is '2, Halogen atom, and n is selected from zero-one, and

two; while simultaneously deformylating a formoxy group at the (3-3 carbon atom of the pregnane nucleus 'to a hydroxyl group by reacting the pregnane derivative with a mercaptan in the presence of an acid-binding agent;

'3. The process or claim 2, wherein'theflstart- 'ing compound is 'a'p'r'egiiene derivative.

I 4. The process ofclaim '2, wherein the simultaneous 'thioesterification and d'ef'ormylal'iil'inis accomplished at a pI-Ijbelow about 10.

5. The process of claim 2', wherein the simul- ?taneous thioesteriilcation and 'deformylation is accomplished with ameroaptan'and pyridine." 6. The process of claim 2; wherein the pregnane derivative is 3-formoxylta 5)}cholenic 'acid chloride.

. h rb s r i m a whe'r' i smi ingjcompound is "a pregnadi'ene' derivative; I 8.'The process which includesj thioe'sterify h a pregnenederivative, having 'a C 20- side-chain ja iiormoxy' group at'th'e C53 position of the pregnene nucleus. to ahydroxy group, to give a 3'- hydroxy acyloxy -pregnene' thioester by" .e.acting the preg'nene derivative with a mercaptan the presence 'of an' aci'd bindin g'. agent."

The moms): glam 5 whsrein the tanol s'thioesterification and defprmyllafidn is accomplished t a pI-Ifbelow about "1 0.

. l0. The'prooesso f claiin-fi, wherein the simulitan'eoug I -thio'est'erificationf and v 1d orm ylatlon is accomplished ,w th mercaptan d. pyridine.v

1 5; h 399359 E .5 Wi l m imp 6 nene derivative is 3,11-di1ormoxy- (delta. 5) -nor- UNI cholenic acid chloride. TED STATES PATENTS 12. Ethyl 3-hydroxy-(de1ta. 5J-thioch1orenate. Number Name Date ROBERT E LEVIN. 2,180,095 Strassberger Nov. 14, 1939 V221; JR- 5 OTHER REFERENCES 0 P Jones, Jour. Chem. 800., 95, 1904-1909 (1909). REFERENCES CITED Chakrovarti, Chem. Ahst. 21, page 3192 (1927) A dt,B h 633, 2390- 39 1 The following references are of record in the m m enc te pages 2 3 930) file of this patent: 

1. THE PROCESS WHICH INCLUDES: TRHIOESTERIFYING AN UNSATURATED DERIVATIVE OF THE PREGNANE SERIES, CONTAINING A C 5-6 DOUBLE BOND AND A C-20 SIDECHAIN OF THE FORMULA: -(CH2)N-COX, WHEREIN X IS SELECTED FROM HYDROXYL AND HALOGEN, AND N IS SELECTED FROM ZERO, ONE, AND TWO; WHILE SIMULTANEOUSLY DEFORMYLATING A FORMOXY GROUP AT THE C-3 CARBON ATOM OF THE PREGANE NUCLEUS TO A HYDROXYL GROUP BY REACTING THE PREGNANE DERIVATIVE WITH A MERCAPTAN IN THE PRESENCE OF AN ACID-BINDING AGENT. 